Alzheimer's disease (AD), first described by the Bavarian psychiatrist Alois Alzheimer in 1907, is a progressive neuropsychiatric disorder which begins with short term memory loss and proceeds to loss of cognitive functions, disorientation, impairment of judgment and reasoning and, ultimately, dementia. AD is the most common form of dementia. AD has been estimated to afflict 5 to 11 percent of the population over age 65 and as much as 47 percent of the population over age 85. Moreover, as adults born during the population boom of the 1940's and 1950's approach the age when AD becomes more prevalent, the control and treatment of AD will become an even more significant health care problem.
Cortical atrophy, neuronal loss, region-specific amyloid deposition, neuritic plaques, and neurofibrillary tangles are key neuropathological features in the AD brain. These alterations are thought to be linked to cognitive decline, which clinically defines AD.
The major constituent of the neuritic plaque, beta-amyloid peptides (Abeta), arises from proteolytic cleavage of a larger precursor protein, the amyloid precursor protein (APP) (Kang, et al., 1987; Tanzi, et al., 1987). Abeta is produced by normal cells and can be detected as circulating peptides in the plasma and cerebrospinal fluid (CSF) of healthy humans. APP is a ubiquitously expressed transmembrane glycoprotein, which undergoes proteolysis by several secretases in the processes of ectodomain shedding and regulated intramembrane proteolysis (Wolfe, Curr Top Dev Biol 2003). In the amyloidogenic pathway beta- and gamma-secretases cleave APP into several Abeta isoforms of which Abeta1-42 is regarded to have a direct link to AD since it is a major constituent of extracellular amyloid deposits in the brains of AD patients, and has been shown to be synaptotoxic. APP may also be cleaved in the middle of the Abeta1-42 sequence by alpha-secretase, precluding the formation of full length Abeta and considered to protect from amyloid deposition in the brain (Blennow et al, Nat Rev Neurol 2010, Haass et al, Nat Rev Mol Cell Biol 2007). The alpha-secretase will thus cleave the membrane glycoprotein APP such that the Abeta1-42 is not produced, thus eliminating a harmful amyloidogenic peptide. There might be a very delicate and not well understood balance between the alpha- and gamma-secretases in this membrane close environment and glycosylation may favor alpha-cleavage. The shorter products when produced from the alpha-secretase cleavage, like the Abeta1-16, and most likely the glyco-Abeta 1-X series of glycopeptides could all interfere with the deposition process—but how such a protective effect would work is not know; interfering with a spontaneous aggregation, or with a facilitator in solution or close to or associated with the membrane. Also, clearance of formed amyloidegenic Abeta 1-42 by the action of several peptidases, including neprilysin and insulin degrading enzyme, is believed to counteract amyloid build-up. In general, the proteolytic destiny and half-life of proteins may not only be governed by primary sequences and the availability of proteases, but also by post-translational modifications such as glycosylations, which may block a protease from accessing its target proteolytic site. This has been described for a few proteins (Marinaro et al, Eur J Biochem 2000, Semenov et al, Clin Chem 2009, Gram Schjoldager K T et al., J Biol Chem 2010).
A biomarker is an objective measure of a biological or pathogenic process that can be used to evaluate disease risk or prognosis, to guide clinical diagnosis, or to monitor therapeutic interventions. Since the CSF is in direct contact with the extracellular space of the brain, biochemical changes in the brain are reflected in the CSF. Today, there are three CSF biomarkers for AD that have been evaluated in numerous studies, showing a diagnostic accuracy of 80-85% (Blennow et al. Nat Rev Neurol 2010; 6:131-144). Since this figure is too low for such a common and severe disease as AD there is a need for additional biomarkers that will improve the diagnostic performance. Further, a biomarker should reflect a specific pathogenic process of the disease.
As AD is a growing social and medical problem, there is a strong need for sensitive and specific methods for early diagnosing or prognosing said disease in subjects as well as for introduction of new methods of treatment.
There is currently no treatment for AD that can reverse or slow down the disease progression. AD represents a major health problem and an effective drug treatment of the disease would represent a major breakthrough.
Thus it was an object of the invention to provide new ways of diagnosing, prognosing, preventing and treating AD.